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7335671 
Journal Article 
Changes in the central component of the hypothalamus-pituitary-thyroid axis in a rabbit model of prolonged critical illness 
Mebis, L; Debaveye, Y; Ellger, B; Derde, S; Ververs, EJ; Langouche, L; Darras, VM; Fliers, E; Visser, TJ; Van Den Berghe, G 
2009 
Yes 
Critical Care
ISSN: 1364-8535
EISSN: 1466-609X 
BMC 
LONDON 
13 
5 
R147 
English 
19747372 
WOS:000272226000006 
Introduction: Prolonged critically ill patients reveal low circulating thyroid hormone levels without a rise in thyroid stimulating hormone (TSH). This condition is labeled "low 3,5,3'-tri-iodothyronine (T3) syndrome" or "nonthyroidal illness syndrome (NTI)" or "euthyroid sick syndrome". Despite the low circulating and peripheral tissue thyroid hormone levels, thyrotropin releasing hormone (TRH) expression in the hypothalamus is reduced and it remains unclear which mechanism is responsible. We set out to study whether increased hypothalamic T3availability could reflect local thyrotoxicosis and explain feedback inhibition-induced suppression of the TRH gene in the context of the low T3syndrome in prolonged critical illness.Methods: Healthy rabbits were compared with prolonged critically ill, parenterally fed animals. We visualized TRH mRNA in the hypothalamus by in situ-hybridization and measured mRNA levels for the type II iodothyronine diodinase (D2), the thyroid hormone transporters monocarboxylate transporter (MCT) 8, MCT10 and organic anion co-transporting polypeptide 1C1 (OATP1C1) and the thyroid hormone receptors α (TRα) and β (TRβ) in the hypothalamus. We also measured the activity of the D2 and type III iodothyronine deiodinase (D3) enzymes.Results: In the hypothalamus of prolonged critically ill rabbits with low circulating T3 and TSH, we observed decreased TRH mRNA, increased D2 mRNA and increased MCT10 and OATP1C1 mRNA while MCT8 gene expression was unaltered as compared with healthy controls. This coincided with low hypothalamic thyroxine (T4) and low-normal T3concentrations, without a change at the thyroid hormone receptor level.Conclusions: Although expression of D2 and of the thyroid hormone transporters MCT10 and OATP1C1 were increased in the hypothalamus of prolonged critical ill animals, hypothalamic T4and T3content or thyroid hormone receptor expression were not elevated. Hence, decreased TRH gene expression, and hereby low TSH and T3 during prolonged critical illness, is not exclusively brought about by hypothalamic thyrotoxicosis, and infer other TRH suppressing factors to play a role. © 2009 Mebis et al.; licensee BioMed Central Ltd. 
iodothyronine diodinase type II; liothyronine; monocarboxylate transporter; monocarboxylate transporter 10; monocarboxylate transporter 8; organic anion co transporting polypeptide 1C1; organic anion transporter; oxidoreductase; protirelin; thyroid hormone receptor alpha; thyroid hormone receptor beta; thyroxine; unclassified drug; iodide peroxidase; iodothyronine deiodinase type II; iodothyronine deiodinase type III; organic anion transporter; protirelin; RNA; animal experiment; animal model; animal tissue; article; controlled study; critical illness; gene expression; gene repression; hormone blood level; hypophysis thyroid system; male; negative feedback; nonhuman; nucleotide sequence; priority journal; rabbit; thyrotoxicosis; animal; comparative study; DNA sequence; euthyroid sick syndrome; fluorescence; genetics; hypophysis; hypothalamus; isolation and purification; metabolism; methodology; pathophysiology; polymerase chain reaction; secretion; thyroid gland; Animals; Critical Illness; Euthyroid Sick Syndromes; Fluorescence; Hypothalamus; Iodide Peroxidase; Male; Models, Animal; Organic Anion Transporters; Pituitary Gland; Polymerase Chain Reaction; Rabbits; RNA; Sequence Analysis, DNA; Suppression, Genetic; Thyroid Gland; Thyrotoxicosis; Thyrotropin-Releasing Hormone